Quinapril prevents restenosis after coronary stenting in patients with angiotensin-converting enzyme D allele.

Restenosis after coronary artery stent implantation is attributed chiefly to intimal hyperplasia, which is prevented experimentally by angiotensin-converting enzyme (ACE) inhibitors. Therefore, the present study investigated whether the effect of quinapril, a tissue-specific ACE inhibitor, on the prevention of coronary restenosis differs according to ACE polymorphism. One hundred consecutive patients with successful stent implantation were randomly assigned to quinapril and control groups. Both follow-up angiography and ACE polymorphism analysis were obtained from 92 patients (control, 46; quinapril treatment, 46). The prevalence of risk factors did not differ statistically according to quinapril treatment or ACE genotypes. There was no statistically significant difference in the occurrence of restenosis 6 months after stenting between the groups. Quantitative coronary angiography revealed that quinapril treatment resulted in significantly higher minimal lumen diameter and significantly lower percent diameter stenosis (22.9 +/- 22.6 vs 37.1 +/- 19.7% in the control group, p < 0.05) in patients with the D allele although there was no difference in those with the II genotype. In addition, intravascular ultrasound revealed that quinapril treatment significantly prevented the loss of minimal lumen cross-sectional area and the increase in percent area stenosis (34.5 +/- 14.0 vs 53.3 +/- 16.4% in the control group, p < 0.05) in patients with the D allele compared to those with the II genotype. These results suggest that the administration of ACE inhibitors for the attenuation of lumen loss after coronary stent implantation is best for subjects with the D allele of the ACE genotype.     

Development of overt hemolytic anemia after splenectomy for thrombocytopenia in Evans syndrome with negative Coombs test

A 69-year-old man was diagnosed as having idiopathic thrombocytopenic purpura (ITP) in April 2000, and treated with prednisolone (PSL) without effect. Splenectomy performed in June 2000 had only a transient and marginal influence on his platelet count. Two months later, he developed autoimmune hemolytic anemia (AIHA) without Coombs test positivity, and his diagnosis was changed to Coombs-negative Evans syndrome. Treatment with PSL led to recovery of his hemoglobin level, but not his platelet count. Although the mechanism responsible for development of AIHA after splenectomy in this patient with ITP remains unknown, close observation is required for any association with other autoimmune diseases such as SLE.     

Clinical effect of continuous infusion of meropenem on bacterial pneumonia in the elderly]

We studied the clinical effect of continuous infusion over 24 hours of meropenem (MEPM) on bacterial pneumonia in the elderly (over 65). The subjects were 26 patients (community-acquired pneumonia: moderate, n = 9; severe, n= 4; hospital-acquired pneumonia: group III, n = 13) whose performance status was 3 or 4. MEPM 1.0g/day was infused continuously for 7-14 days, and its clinical efficacy, bacteriological efficacy, and side effects were examined prospectively. It was effective in 23 of the 26 patients (community-acquired pneumonia: moderate, 8/9; severe, 3/4; hospital-acquired pneumonia: group III, 12/13; efficacy rate: 88.5%). Bactericidal effects were obtained in 3 strains of Klebsiella pneumoniae, 2 strains of Streptococcus pneumoniae, 2 strains of methicillin-sensitive Staphlococcus aureus, 1 strain of Streptococcus agalactiae and 1 strain of Proteus mirabilis, but not in 2 strains of methicillin-resistant S. aureus, 1 strain of Pseudomonas aeruginosa and 1 strain of Serratia marcescens. Mild abnormal laboratory findings were observed in 2 patients: elevation of GPT, gamma-GTP, BUN and elevation of ALP. Based on the above, continuous infusion of MEPM on bacterial pneumonia in the elderly obtained excellent clinical effects. Further study is needed to compare the efficacy of continuous versus intermittent administration of MEPM.     

P66shc regulates endothelial NO production and endothelium-dependent vasorelaxation: implications for age-associated vascular dysfunction

The p66shc adaptor protein mediates age-associated oxidative stress. We examined the role of p66shc in endothelial nitric oxide synthase (eNOS) signaling. Overexpression of p66shc inhibited eNOS-dependent NO production. RNAi-mediated down-regulation of endogenous p66shc led to activation of the proto-oncogene ras, and Akt kinase, with a corresponding increase in phosphorylation of eNOS at S1177 (S1179 on bovine eNOS). In rat aortic rings, down-regulation of p66shc suppressed the vasoconstrictor response to phenyephrine that was abrogated by treatment with the NOS inhibitor l-NAME, and enhanced vasodilation induced by sub-maximal doses of acetylcholine. These findings highlight a pivotal role for p66shc in inhibiting endothelial NO production, and endothelium-dependent vasorelaxation, that may provide important mechanistic information about endothelial dysfunction seen with aging.     

Spontaneous rupture of liver hemangioma: Risk factors for rupture

We report a case of spontaneous rupture of a giant cavernous hemangioma of the liver arising from the caudate lobe, with extrahepatic growth, in a 67-year-old man. At emergency laparotomy, partial resection of the caudate lobe was performed and the hemangioma was found to measure 13 ×12×8 cm. The patient had a 10-year history of severe asthma requiring steroid therapy. To investigate the risk factors for spontaneous rupture of hepatic hemangioma, we compared the characteristics of patients with ruptured and non-ruptured lesions showing extrahepatic growth reported in the Japanese literature. Lesions with a diameter ≥4 cm located on the surface of the liver or showing extrahepatic growth appear to have a high risk of spontaneous rupture if the patient receives steroid therapy for a coexisting disorder. Even in patients who have not received steroid therapy, hemangiomas≥7–8 cm in diameter located in the left lobe with extrahepatic growth may also have a high risk of rupture. The treatment of hepatic hemangioma should be decided on the basis of the size and the location, and on the requirement for steroid therapy.     

Use of prostaglandin I2 analog in treatment of massive hepatic necrosis associated with endothelial cell injury and diffuse sinusoidal fibrin deposition

Endothelial cell damage causes massive hepatic necrosis as a result of fibrin deposition in the hepatic sinusoids. When a stable analog of prostaglandin I₂, beraprost sodium, was administered to rats given either dimethylnitrosamine, carbon tetrachloride, or endotoxin followingCorynebacterium parvum administration, the hepatic necrosis produced in each was attenuated, but to a greater extent in the dimethylnitrosamine and endotoxin/Corynebacterium parvum models, where fibrin deposition in the hepatic sinusoids occurs, as compared to the carbon tetrachloride model, where such fibrin deposition does not occur. Beraprost sodium reduced the expected increase of portal venous pressure in the endotoxin/Corynebacterium parvum model without affecting plasma thrombin-antithrombin III complex levels. Beraprost sodium also significantly reduced cell killing of both isolated rat hepatocytes and hepatic sinusoidal endothelial cells exposed totert-butyl hydroperoxide when compared to controls. Beraprost sodium could prove to be a therapeutic candidate for the treatment of hepatic necrosis, particularly in cases associated with fibrin deposition in the hepatic sinusoids because of its fibrin clot-clearning action.     

Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo-like left ventricular dysfunction

OBJECTIVES: We sought to assess myocardial perfusion and metabolism in patients with peculiar transient asynergy, which consisted of basal normokinesia and apical akinesia of the left ventricle (LV) at the same time. BACKGROUND: This asynergy has been widely called "tako-tsubo-like LV dysfunction" in Japan, but little is known about its pathophysiology. METHODS: We performed rest tallium-201 ((201)Tl) and iodine-123-beta-methyl-p-iodophenyl penta-decanoic acid ((123)I-BMIPP) dual-isotope myocardial single-photon emission computed tomography (SPECT) in 14 patients with tako-tsubo-like LV dysfunction. The LV was divided into 17 segments, and each segment was graded with scores between normal uptake (0) and defect (4). We also measured the Thrombolysis in Myocardial Infarction trial (TIMI) frame count in 28 patients and 20 control subjects. RESULTS: Early SPECT (5 +/- 3 days) revealed that the total defect score value with BMIPP was significantly higher than reduced uptake with (201)Tl (p < 0.01). Reduced uptake of BMIPP was observed in parallel with an apical akinetic region and usually involved uptake of (201)Tl. This discrepancy improved gradually during the follow-up period (29 +/- 6 days) (p = 0.36). Compared with control subjects, patients had a TIMI frame count that was significantly higher in all coronary arteries immediately after onset. This higher TIMI frame count decreased but was sustained even after resolution of tako-tsubo-like LV dysfunction. CONCLUSIONS: Our data suggest that myocardial fatty acid metabolism is more severely impaired than myocardial perfusion, in parallel with an apical akinetic region during the early phase, and that impaired multivessel coronary microcirculation is involved, at least in part, in tako-tsubo-like LV dysfunction.     

Application of real-time RT-PCR to quantifying gene expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human abdominal aortic aneurysm

BACKGROUND: The relative expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), key regulators in remodeling of extracellular matrix, are considered to play a pivotal role in the development of abdominal aortic aneurysm (AAA). However, few data exist regarding quantitative assessment of their expression in clinical settings. METHODS: In 22 patients with AAA who underwent graft replacement, tissue samples of the AAA and non-dilated aorta were obtained. Using a real-time RT-PCR method that enabled quantitative measurement of mRNA levels in small tissue samples, we determined gene expression levels of MMPs and TIMPs relative to that of glutaraldehyde 3-phosphate dehydrogenase in each sample. RESULTS: The expression levels of the MMP-1 and -3 genes were significantly augmented in AAA compared with non-dilated regions (4.48 +/- 2.01 versus 0.26 +/- 0.12, P < 0.01 and 1.89 +/- 1.00 versus 5.01 +/- 0.97, P < 0.05, respectively). Although genes for TIMP-1, -2 and -3 tended to be upregulated in AAA, relative expression levels of MMP-1 to TIMP-1, MMP-1 to TIMP-2, MMP-1 to TIMP-3, and MMP-3 to TIMP-2 were still higher in AAA than in non-dilated regions (1.12 +/- 0.63 versus 0.10 +/- 0.03, 4.13 +/- 1.12 versus 0.43 +/- 0.11, 1.61 +/- 0.59 versus 0.14 +/- 0.03, and 7.81 +/- 1.60 versus 2.56 +/- 0.76, respectively, P < 0.05). CONCLUSION: These results demonstrate that the present real-time RT-PCR method is reliable for the determination of mRNA levels in small samples of vascular tissue and that disproportional expression of both MMP-1 and MMP-3 relative to TIMPs relates pathologically to the evolution of AAA.     

Demonstration of cooperative contribution of MET- and EGFR-mediated STAT3 phosphorylation to liver regeneration by exogenous suppressor of cytokine signalings

BACKGROUND/AIMS: As conditional knockout mice for stat3 are impaired in liver regeneration after partial hepatectomy while those for gp130 have defects in early STAT3 phosphorylation but have normal DNA synthesis, late STAT3 phosphorylation induced independently of gp130 seems to be essential for liver regeneration. Since HGF and EGF can activate STAT3 via gp130-independent MET and EGFR, respectively, we assumed that these factors account for STAT3-dependent liver regeneration. Here, we investigated this hypothesis by introducing suppressor of cytokine signaling (SOCS)-1 and SOCS3, potent negative regulators of STAT3 signaling, selectively in hepatocytes. METHODS: We generated recombinant adenoviruses expressing socs1 and socs3. RESULTS: Hepatocytes infected with socs1-virus lacked STAT3 phosphorylation in response to IL-6 and HGF, while cells infected with socs3-virus lacked the response to all of IL-6, HGF and EGF, indicating that those SOCS proteins differently regulate EGFR signaling. Mice infected with socs3-virus exhibited severe and persistent impairment while those with socs1-virus showed only delayed regeneration, indicating requirement of both MET and EGFR signalings. CONCLUSIONS: These results clearly demonstrated that MET- and EGFR-mediated STAT3 signalings cooperatively contribute to liver regeneration and could provide new insights into tissue homeostasis.